Advertisement

Journal of Neuro-Oncology

, Volume 121, Issue 3, pp 557–563 | Cite as

Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma

  • Jennie W. Taylor
  • Jorg Dietrich
  • Elizabeth R. Gerstner
  • Andrew D. Norden
  • Mikael L. Rinne
  • Daniel P. Cahill
  • Anat Stemmer-Rachamimov
  • Patrick Y. Wen
  • Rebecca A. Betensky
  • Diana H. Giorgio
  • Kellis Snodgrass
  • Alison E. Randall
  • Tracy T. Batchelor
  • Andrew S. Chi
Clinical Study

Abstract

Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7–9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.

Keywords

Glioblastoma Bosutinib Src inhibitor Invasion 

Notes

Acknowledgments

J.W.T is supported by U.S. National Cancer Institute of the National Institutes of Health under Award Number K12CA090354. A.S.C. is supported by a Richard B. Simches Scholars Award and an Early Career Research Award from The Ben and Catherine Ivy Foundation. We thank Gino Ferraro and Carolyn Smith for assistance with immunohistochemistry.

Conflict of interest

J. Taylor, J. Dietrich, E. Gerstner, A. Norden, M. Rinne, D. Cahill, A. Stemmer-Rachamimov, P. Wen, R. Betensky, and A. Chi have no conflict of interest. T. Batchelor has received research funding from Pfizer, Incorporated. D. Giorgio, K. Snodgrass, and A. Randall are employed by Pfizer, Incorporated.

References

  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine 352:987–996. doi: 10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
  2. 2.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. doi: 10.1016/S1470-2045(09)70025-7 PubMedCrossRefGoogle Scholar
  3. 3.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740. doi: 10.1200/JCO.2008.19.8721 PubMedCrossRefGoogle Scholar
  4. 4.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745. doi: 10.1200/JCO.2008.16.3055 PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG, Frame MC (2002) Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling. Nat Cell Biol 4:632–638. doi: 10.1038/ncb829 PubMedGoogle Scholar
  6. 6.
    Irby RB, Yeatman TJ (2002) Increased Src activity disrupts cadherin/catenin-mediated homotypic adhesion in human colon cancer and transformed rodent cells. Cancer Res 62:2669–2674PubMedGoogle Scholar
  7. 7.
    Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, Burns M, Julian B, Peng XP, Hieronymus H, Maglathlin RL, Lewis TA, Liau LM, Nghiemphu P, Mellinghoff IK, Louis DN, Loda M, Carr SA, Kung AL, Golub TR (2009) Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nat Biotechnol 27:77–83. doi: 10.1038/nbt.1513 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Angers-Loustau A, Hering R, Werbowetski TE, Kaplan DR, Del Maestro RF (2004) SRC regulates actin dynamics and invasion of malignant glial cells in three dimensions. Mol Cancer Res MCR 2:595–605Google Scholar
  9. 9.
    Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J, Cheresh DA (1999) Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell 4:915–924PubMedCrossRefGoogle Scholar
  10. 10.
    Weissenberger J, Steinbach JP, Malin G, Spada S, Rulicke T, Aguzzi A (1997) Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice. Oncogene 14:2005–2013. doi: 10.1038/sj.onc.1201168 PubMedCrossRefGoogle Scholar
  11. 11.
    Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661. doi: 10.1021/jm049486a PubMedCrossRefGoogle Scholar
  12. 12.
    Franceschi E, Stupp R, van den Bent MJ, van Herpen C, Laigle Donadey F, Gorlia T, Hegi M, Lhermitte B, Strauss LC, Allgeier A, Lacombe D, Brandes AA (2012) EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma. Neuro-oncology 14:1503–1510. doi: 10.1093/neuonc/nos256 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Reardon DA, Vredenburgh JJ, Desjardins A, Peters KB, Sathornsumetee S, Threatt S, Sampson JH, Herndon JE 2nd, Coan A, McSherry F, Rich JN, McLendon RE, Zhang S, Friedman HS (2012) Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma. J Neurooncol 108:499–506. doi: 10.1007/s11060-012-0848-x PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Lassman AB WM, Gilbert M, Aldape K, Wright J, Wagner H, Brachman D, Malkin M, Mehta M. (2008) Phase 2 trial of dasatinib in patients with recurrent glioblastoma (RTOG 0627) Neuro-oncology 10: abstract MA-30Google Scholar
  15. 15.
    Lassman AB WM, GIlbert MR, Aldape KD, Beumer JJ, Wright J, Takebe N, Puduvalli VK, Hormigo A, Gaur R, Werner-Wask M, and Mehta, MP (2011) Phase II trial of dasatinib in target selected patients with recurrent glioblastoma (RTOG 0627). Neuro-oncology 13: iii 64Google Scholar
  16. 16.
    Lu-Emerson C, Norden AD, Drappatz J, Quant EC, Beroukhim R, Ciampa AS, Doherty LM, Lafrankie DC, Ruland S, Wen PY (2011) Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure. J Neurooncol 104:287–291. doi: 10.1007/s11060-010-0489-x PubMedCrossRefGoogle Scholar
  17. 17.
    Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C (2011) Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118:4567–4576. doi: 10.1182/blood-2011-05-355594 PubMedCrossRefGoogle Scholar
  18. 18.
    Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 30:3486–3492. doi: 10.1200/JCO.2011.38.7522 PubMedCrossRefGoogle Scholar
  19. 19.
    Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, Frost P, Ye F, Boschelli DH, Boschelli F (2003) SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res 63:375–381PubMedGoogle Scholar
  20. 20.
    Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C (2006) In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res 66:11314–11322. doi: 10.1158/0008-5472.CAN-06-1199 PubMedCrossRefGoogle Scholar
  21. 21.
    Amsberg GK, Schafhausen P (2013) Bosutinib in the management of chronic myelogenous leukemia. Biol Targets Ther 7:115–122. doi: 10.2147/BTT.S30182 CrossRefGoogle Scholar
  22. 22.
    Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  23. 23.
    Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, Chiorean EG, Springett GM, Abbas R, Agarwal S, Bardy-Bouxin N, Hsyu PH, Leip E, Turnbull K, Zacharchuk C, Messersmith WA (2012) Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors. Clin Cancer Res 18:1092–1100. doi: 10.1158/1078-0432.CCR-11-2378 PubMedCrossRefGoogle Scholar
  24. 24.
    Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10PubMedCrossRefGoogle Scholar
  25. 25.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  26. 26.
    Lund CV, Nguyen MT, Owens GC, Pakchoian AJ, Shaterian A, Kruse CA, Eliceiri BP (2006) Reduced glioma infiltration in Src-deficient mice. J Neurooncol 78:19–29. doi: 10.1007/s11060-005-9068-y PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Huveldt D, Lewis-Tuffin LJ, Carlson BL, Schroeder MA, Rodriguez F, Giannini C, Galanis E, Sarkaria JN, Anastasiadis PZ (2013) Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. PLoS ONE 8:e56505. doi: 10.1371/journal.pone.0056505 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    (2008) Bosutinib (SK-606) Investigator’s BrochureGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jennie W. Taylor
    • 1
    • 8
  • Jorg Dietrich
    • 1
    • 8
  • Elizabeth R. Gerstner
    • 1
    • 8
  • Andrew D. Norden
    • 2
    • 8
  • Mikael L. Rinne
    • 2
    • 8
  • Daniel P. Cahill
    • 3
    • 8
  • Anat Stemmer-Rachamimov
    • 4
    • 8
  • Patrick Y. Wen
    • 2
    • 8
  • Rebecca A. Betensky
    • 5
  • Diana H. Giorgio
    • 6
  • Kellis Snodgrass
    • 6
  • Alison E. Randall
    • 6
  • Tracy T. Batchelor
    • 1
    • 7
    • 8
  • Andrew S. Chi
    • 1
    • 7
    • 8
  1. 1.Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of NeurologyMassachusetts General Hospital Cancer CenterBostonUSA
  2. 2.Center for Neuro-OncologyDana-Farber/Brigham and Women’s Cancer CenterBostonUSA
  3. 3.Department of Neurosurgery, Stephen E. and Catherine Pappas Center for Neuro-OncologyMassachusetts General Hospital Cancer CenterBostonUSA
  4. 4.Department of PathologyMassachusetts General HospitalBostonUSA
  5. 5.Department of Biostatistics, Harvard School of Public HealthHarvard Medical SchoolBostonUSA
  6. 6.Pfizer, IncorporatedNew YorkUSA
  7. 7.Translational Neuro-Oncology LaboratoryMassachusetts General HospitalBostonUSA
  8. 8.Harvard Medical SchoolBostonUSA

Personalised recommendations